SPARC Promotes Aerobic Glycolysis and 5-Fluorouracil Resistance in Colorectal Cancer Through the STAT3/HK2 Axis

IF 2.9 2区医学 Q2 ONCOLOGY

Cancer Medicine Pub Date : 2025-05-25 DOI:10.1002/cam4.70972

Jingrong Xiang, Huan Zhang, Kanger Shen, Jie Feng, Kexi Yang, Tongguo Shi, Qinhua Xi

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引用次数: 0

Abstract

Background

Chemotherapy has been used extensively in the clinic to treat colorectal cancer (CRC). Nevertheless, cancer cells usually develop chemoresistance under chemotherapy stress, leading to treatment failure. At present, the mechanism of chemoresistance in patients with CRC is not fully understood.

Methods

Firstly, Secreted protein acidic and rich in cysteine (SPARC) expression and prognosis in CRC clinical samples were investigated using tissue microarray (TMAs) and GEPIA databases. Subsequently in vitro, SPARC knockdown or overexpression was used to explore the role of SPARC in 5-fluorouracil (5-FU) resistance in CRC cell lines. Western blot or RT-qPCR was used to analyze the downstream molecules and pathways regulated by SPARC. The contents of glucose and lactic acid were determined by Elisa. In vivo a xenograft tumor model was constructed to verify the function of SPARC in 5-FU chemoresistance.

Results

This study revealed a correlation between 5-FU resistance in CRC and the expression of SPARC. The elevated SPARC expression in CRC tissues was linked to a poor prognosis for CRC patients. SPARC knockdown in CRC cells significantly suppressed aerobic glycolysis and 5-FU resistance, whereas SPARC overexpression had cancer-promoting effects. Additionally, SPARC increased 5-FU resistance through the Signal transducer and activator of transcription 3 (STAT3)/Hexokinase-2 (HK2) pathway. The impact of SPARC on 5-FU resistance was eliminated both in vitro and in vivo by blocking HK2 or STAT3 signaling.

Conclusion

Our results confirmed that SPARC affects the chemoresistance of CRC to 5-FU through the STAT3/HK2 axis and is one of the indispensable factors affecting the development of 5-FU resistance in CRC.

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SPARC通过STAT3/HK2轴促进结直肠癌的有氧糖酵解和5-氟尿嘧啶耐药

化疗已广泛应用于临床治疗结直肠癌（CRC）。然而，在化疗压力下，癌细胞通常会产生化疗耐药，导致治疗失败。目前，结直肠癌患者的化疗耐药机制尚不完全清楚。方法首先利用组织芯片（TMAs）和GEPIA数据库，研究CRC临床标本中酸性和富含半胱氨酸的分泌蛋白（SPARC）的表达与预后。随后，在体外通过SPARC敲低或过表达来探讨SPARC在结直肠癌细胞系5-氟尿嘧啶（5-FU）耐药中的作用。采用Western blot或RT-qPCR分析SPARC调控的下游分子及通路。采用Elisa法测定葡萄糖和乳酸的含量。在体内构建异种移植肿瘤模型来验证SPARC在5-FU化疗耐药中的作用。结果本研究揭示了结直肠癌5-FU耐药性与SPARC表达的相关性。结直肠癌组织中SPARC表达升高与结直肠癌患者预后不良有关。在结直肠癌细胞中，SPARC敲低可显著抑制有氧糖酵解和5-FU耐药性，而SPARC过表达具有促癌作用。此外，SPARC通过信号传导和转录激活因子3 (STAT3)/己糖激酶-2 （HK2）途径增加5-FU耐药性。通过阻断HK2或STAT3信号通路，在体内和体外均可消除SPARC对5-FU耐药性的影响。结论我们的结果证实，SPARC通过STAT3/HK2轴影响结直肠癌对5-FU的化疗耐药，是影响结直肠癌5-FU耐药发展不可或缺的因素之一。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.